January 2008

4.

Heterocyclic Chemistry: Exam Questions and Model Answers

Answer ALL of the following parts.

(a)

The structure of benzonitrile oxide is given below.

O
CO2Me
MeO2C

benzonitrile oxide

CO2Me

dimethyl maleate

MeO2C
dimethyl fumarate

(i)

Give the reagents that are needed to make benzonitrile oxide from
benzaldehyde.
(ii) Work out the cycloaddition product of benzonitrile oxide with dimethyl
maleate and dimethyl fumarate showing clearly the stereochemistry in
each case.
(2, 6 marks)
(b) Consider the scheme below:
MeO

MeO

H+

step 1
N

NH2

MeO
NH

step 2

A Ph

B Ph

(i) Give the reactant and reagent needed in step 1.

(ii) Show the mechanism for step 2.
(iii) What would happen to the rate of reaction of step 2 if the methoxy group
in A was replaced by a nitro group? Explain your answer.
(iv) In step 2 an alternative product to B may be formed in theory. Draw this
product and explain why it is not formed in practice.
(1, 3, 2, 4 marks)
(c)

Consider the following scheme and work out the structures of C and D.

Me

N
O
o

85 C
OMe

C
C14H19NO2

H2
Pd-C

D
C14H21NO2
-1
max 3400 cm
(broad)

(4, 3 marks)

January 2008

Heterocyclic Chemistry: Exam Questions and Model Answers

Q4 Model answer
(a)

(i)
O

HO

NH2OH

e.g.
NCS

HO

e.g.
Et3N

O N C Ph

Cl

Ph

Ph

Ph

NCS = N-chlorosuccinimide

(ii)
O

MeO2C
MeO2C

CO2Me

CO2Me
MeO2C

MeO2C

Ph

() syn isomer

cis alkene

MeO2C
MeO2C

N
Ph

() anti isomer

trans alkene

(b)
MeO

MeO

MeO

H+

step 1
N

NH2

NH

step 2

A Ph

(i)

PhCHO / catal. H+.

(ii)

Mechanism for step 2.

MeO

H+

MeO

B Ph

MeO

MeO

NH

Ph

NH

NH
H

Ph

Ph

Ph

(iii) Switching from +M OMe to M NO2 makes the ring less nucleophilic and so the
rate of cyclisation would decrease.
(iv) Cyclisation ortho to the OMe is disfavoured due to steric factors.
Ph

H
N

MeO

(c)
exo attack
H
Me

N
O
85 oC
OMe

Me

N
O
H
OMe
C

H
H2
Pd-C

Me

N
H
OH

H
OMe

max

3400 cm-1

January 2009
4.

Heterocyclic Chemistry: Exam Questions and Model Answers

Answer all of the following parts.

(a)

In the Fischer indole synthesis acetone and phenylhydrazine (PhNHNH 2) react

to give 2-methylindole (A). Using this fact and the data for C provided, work out
the structures of B, C and D.

O
NHNH2

H3C

CH3

N
H

CH3

Br
O
NHNH2
NHNH2

O2N

data for C: C5H8O3,

B
C12H12BrN

max(CHCl3)

D
C11H10N2O4

C
1731 and 1751 cm-1,

4.2 (2H, q), 2.2 (3H, s), 1.3 (3H, t)

(10 marks)
(b)

Explain why the reaction of phenylhydrazine with butan-2-one may lead to two
isomeric indoles. A full mechanism of the Fischer indole synthesis is not
required, though you should give the key intermediates to explain your answer.
(5 marks)

(c)

Using an appropriate example and reaction mechanism, describe one method

that can be used for the generation of nitrile oxides.
(5 marks)

(d)

For the following cycloaddition reactions involving 1,3-dipoles, identify EITHER

the structures of intermediate E and product F, OR the structures of
intermediate G and product H. Indicate clearly the relative stereochemistry of
the product.
CO2Et

Ph
N
Ph

NH

Et3N

CO2Et

E
Cl
1. NaNO2 / HCl

Ph NH2

2. NaN3
(sodium azide)

Me
G

F
C21H22N2O4

Me
H
C10H13N3

(5 marks)

January 2009

Heterocyclic Chemistry: Exam Questions and Model Answers

Q4 Model answer
(a)
Br
O
NHNH2

+
Br
1731 and 1751 cm-1

4.2 (2H, q)

2.2 (3H, s)

O2N

1.3 (3H, t)

NHNH2

O2N

N
H
B

N
H

Br

O
O

C = C5H8O3

(b)

Tautomerisation of the hydrazone can lead to two different enamines, and thus two
different indoles. Depending on the acid catalyst the ratio may be altered, though
typically the more substiututed enamine is favoured.
more substituted enamine

NHNH2
+

N N
H H

N
H

N N
H H

N
H

N N
H
O

less substituted enamine

(c)

E.g.
O

NH2OH

HO

e.g.
NCS

H
Ph

HO

e.g.
Et3N

O N C Ph

Cl
Ph

Ph

NCS = N-chlorosuccinimide

(d)
Ph
NH
N
Ph

Et3N

Ph
N
N

CO2Et
CO2Et
cis

Cl

Ph
N
N

CO2Et
Ph
()-F

Ph
E

Me

N
1. NaNO2 / HCl
Ph NH2

2. NaN3
(sodium azide)

N
N
Ph
G

CO2Et
syn

N
Me
trans

Me

anti

N
Me
Ph
()-H

January 2010
4.

Heterocyclic Chemistry: Exam Questions and Model Answers

Answer part (a) and three from parts (b)-(e).

(a)

Consider the sequence below and identify compounds B, D, E and F.

NH2OH
NaOAc
O

Cl

NCS

B
C6H13NO

NOH

Et3N
F
C10H18O3

Raney-Ni, H2
MeOH-H2O

O
E
C10H17NO2

D
C6H11NO

NCS = N-chlorosuccinimide

(10 marks)

(b)

Nitration of quinoline using a mixture of nitric and sulfuric acids gives a mixture
of mainly 5-nitro and 8-nitroquinoline. Give an explanation as to why these
isomers are formed preferentially.
(5 marks)

(c)

When treated with 13C-labelled formaldehyde (methanal, *CH2=O) the indole

derivative G undergoes a Pictet-Spengler reaction to give products H and H in
which the labelled carbon (*) is found distributed equally between C1 and C4.
Account for this observation.

N
H

H2C=O

NMe
NHMe

N
H

NMe
NMe

+
N
H

NMe
NMe
H'

(5 marks)
(d)

Explain why the reaction of phenylhydrazine with cyclohexa-1,3-dione leads to

only one indole product I, as shown below. A full mechanism of the Fischer
indole synthesis is not required, though you should give the key intermediates
to explain your answer.
O
O
NHNH2

H+

N
H
I

(5 marks)

(Question 4 continued overleaf)

5

January 2010

Heterocyclic Chemistry: Exam Questions and Model Answers

(Question 4 continued)

(e)

Work out the cycloaddition product of benzonitrile oxide (J) with (i) dimethyl
maleate, K; (ii) dimethyl fumarate, L. Show clearly the stereochemistry in each
case.

O
CO2Me
MeO2C

CO2Me

MeO2C

(5 marks)
Q4 Model answer
(a)
O
H
N

NOH
B
C6H13NO

O
C5H11
F
C10H18O3

C5H11
E
C10H17NO2

D
C6H11NO

OH

(b)
5

H+

pyrido ring resistant

to electrophilic attack

N
H

E+
E

N
E

N
E

delocalisation of charge in intermediate arising from C5 or C8 attack provides stability

without disrupting aromaticity of the pyrido ring (unlike with C6 or C7 attack)
E
N

January 2010

Heterocyclic Chemistry: Exam Questions and Model Answers

(c)

H2C=O

NMe
NHMe

N
H

NMe
NMe

N
H

N H C
2
H

NMe
NMe
H'

attack at C2
Me
N
NMe

NMe
NMe

N
H

iminium ion

N
H

attack at C2

N H C
2
H

electrophilic attack at C3 preferred!

symmetrical intemediate formed

NMe
NMe

position of
isotopic label
scrambled

(d)
O
O
NHNH2

+
N
H

H
N

O
H
N

symmetry in diketone means

only one hydrazone possible

N
H

>>

N
H

H
N

N
H

conjugated ene-hydrazine more stable than other

possible isomer, hence only one indole formed

(e)
MeO2C
MeO2C

CO2Me
MeO2C

cis alkene

CO2Me

N
Ph

() syn isomer

MeO2C
trans alkene

MeO2C
MeO2C

N
Ph

() anti isomer

January 2011
4.

Heterocyclic Chemistry: Exam Questions and Model Answers

Answer part (a) and any THREE from parts (b) (e).
(a)

Consider the reaction below and answer the following questions.

Cl
H2N

NH

O
+

CH3CO2H

(b)

+
D (20%)
C16H17ClN2O

H
A

C (23%)
C16H17ClN2O

(i)

Work out structures for isomers C and D arising from the Fischer indole
reaction between phenyl hydrazine A and ketoamide B.

(ii)

Given that the major product is a pyrrolo[3,2-c]carbazole and the minor

product is a pyrrolo[2,3-b]carbazole identify which of the structures you
have drawn is C and which is D.

(iii)

Using a brief mechanistic argument explain why two isomers arise from
this reaction.
(4, 2, 4 marks)

Given that in the Doebner-von Miller quinoline synthesis trans-but-2-enal and

aniline react to give 2-methylquinoline (E), formulate the products F and G.
O
+

NH2

CH3

EtO2C

CH3

O
+
NH2

H3C

Cl
+

NH2

(5 marks)

(Question 4 continued overleaf)

January 2011

Heterocyclic Chemistry: Exam Questions and Model Answers

(Question 4 continued)

(c)

Using the example below, describe the advantages and disadvantages of the
isoxazoline route to forming the -hydroxy ketone (aldol product) H.
EtCH=CHCO2Et
N O

Ph

EtO2C

O
N

OH O

Ti3+ (aq)

Ph

EtO2C

Et

Et

Ph

(5 marks)
(
(d)

Using benzonitrile oxide (PhCNO), or an example of you own choice, describe

one method that can be used to generate a nitrile oxide from a stable precursor.
Give a mechanism for the step in which the 1,3-dipole is generated.
(5 marks)

(e)

For the following cycloaddition reactions involving 1,3-dipoles, identify EITHER

the structures of intermediate I and product J, OR the structures of intermediate
K and product L. Indicate clearly the relative stereochemistry of the product.
Ph
N
Ph

NH

Et3N

O
J
(C17H12N2O3)

I
Cl

1. NaNO2 / HCl
Ph NH2

2. NaN3

EtO2C
K

CO2Et

L
(C14H17N3O4)

(5 marks)

January 2012
4.

Heterocyclic Chemistry: Exam Questions and Model Answers

Answer part (a) and any THREE from parts (b) (e).
(a)

Consider the reaction below and answer the following questions.

H

H
O

reagents
HON

NaOCl

C
C10H15NO3

HO

H H

reagents

O
H

D
C10H15NO3

(i)

Suggest reagents for the transformation A B.

(ii)

Identify dipole C and cycloadduct D showing clearly any relevant

stereochemistry.

(iii)

Suggest suitable reagents for the transformation D E, and give the

product that would arise if D was reacted with H2 / Pd-C.
(1, 5, 4 marks)

(b)

When treated with 13C-labelled formaldehyde (methanal, *CH2=O) the indole

derivative F undergoes a Pictet-Spengler reaction to give products G and G in
which the labelled carbon (*) is found distributed equally between C1 and C4.
Account for this observation.

N
H

NMe
NHMe

H2C=O
N
H

NMe
NMe

+
N
H

NMe
NMe
G'

(5 marks)
(c)

Identify product J, which is obtained when phenylhydrazine (H) is reacted with

ketone I in a Fischer indole reaction, and explain why only one structural isomer
is formed. A mechanism of the reaction is not required, but you should show
relevant intermediate(s) to help justify your answer.
NHNH2
H

H+

O
Ph

J
C15H13N

(Question 4 continued overleaf)

(5 marks)
10

January 2012

Heterocyclic Chemistry: Exam Questions and Model Answers

(Question 4 continued overleaf)

(d)

Given that in the Dbner-von Miller quinoline synthesis crotonaldehyde (transbut-2-enal) and aniline react to give 2-methylquinoline (K), work out the
structures of products L and M.
O
+
NH2

CH3

CH3

K
NH2

CH3

L
C11H11NO

MeO
Br
NH2

M
C12H12BrN

+
H3C

Et

(5 marks)
(e)

Indole N was heated with potassium carbonate in acetonitrile to give a low

melting point, crystalline solid, O. Derive the structure of O and explain its
formation.
Br
N

N
H

K2CO3, MeCN
O
C10H9N

(5 marks)

11

January 2013

Heterocyclic Chemistry: Exam Questions and Model Answers

Q1c (compulsory)
Consider the sequence below and answer all of the following questions:

H+
40 oC

O
OEt

NH2
CH3
J

CH3
K

N
H

150 oC

CH3
CH3

N
H

CH3

L
POCl3
Cl

CH3NH2

N
C12H13ClN2

Cl2

M
C11H9Cl2N

heat

CH3

CH3

(i)

Identify a suitable reactant I that may be used to convert J into K.

(ii)

Work out the structure of L, an isomer of L, which is formed when application of

the reaction conditions in the first two steps is reversed.

(iii)

Work out the structures of products M and N.

(2, 4, 4 marks)

Q4 (optional)
4.

Answer THREE of the following parts (a) to (d).

(a)

Draw the cycloaddition product of benzonitrile oxide (A) with (i) dimethyl
maleate (B); (ii) dimethyl fumarate (C). Show clearly the relative
stereochemistry in each case.

O
CO2Me
MeO2C

CO2Me

MeO2C

(5 marks)

(Question 4 continued overleaf)

12

January 2013

Heterocyclic Chemistry: Exam Questions and Model Answers

(Question 4 continued)
(b)

Consider the scheme below and work out the structure of Pictet-Spengler
product E. Explain briefly why the particular isomer identified is formed
preferentially.
OMe

H+

NC

C23H20N2O
E

N
D

Ph

(5 marks)

(c)

Explain why the reaction of the phenylhydrazine F with cyclohexa-1,3-dione (G)

leads to only one indole product, H. A mechanism of the Fischer indole
synthesis is not required, but key intermediates should be drawn.
O

O
NHNH2

H+

MeO

O
MeO

N
H

(5 marks)
(d)

Consider the following scheme and work out the structure of I (including
stereochemistry). Suggest reagents needed to convert I into J.
OH

N O
I
o

85 C
MeO

C13H17NO2

reagents

N
H
MeO

(5 marks)

13